US6130072A - Osmotically controlled fermentation process for the preparation of acarbose - Google Patents

Osmotically controlled fermentation process for the preparation of acarbose Download PDF

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US6130072A
US6130072A US08/924,157 US92415797A US6130072A US 6130072 A US6130072 A US 6130072A US 92415797 A US92415797 A US 92415797A US 6130072 A US6130072 A US 6130072A
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fermentation
osmolality
nutrient solution
acarbose
culture
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Jurgen Beunink
Michael Schedel
Ulrich Steiner
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Bayer Intellectual Property GmbH
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Bayer AG
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Assigned to BAYER SCHERING PHARMA AKTIENGESELLSCHAFT reassignment BAYER SCHERING PHARMA AKTIENGESELLSCHAFT A CHANGE OF NAME WAS RECORDED ON AUGUST 28, 2009 AT REEL/FRAME 023148/0924. THE ADDRESS SHOULD ALSO HAVE BEEN CHANGE FROM LEVERKUSEN GERMANY 51368 TO BERLIN, GERMANY 13353 Assignors: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • Acarbose is a potent ⁇ -glucosidase inhibitor, which is used as an orally administered antidiabetic drug under the trade name Glucobay® for the therapy of diabetes mellitus.
  • the active compound is obtained by fermentation; the producer organism is the soil bacterium Actinoplanes spec. SE 50/110, or mutants derived therefrom.
  • the fermentative preparation of an active compound such as acarbose is not economic without optimization of the process. It is as a rule therefore necessary to considerably improve the fermentation with regard to the space-time yields which can be achieved.
  • An improvement in yield may be achieved by various processes known to those skilled in the art. These include, for example, mutagen treatment of the producer organism and selection of higher-producing mutants from the surviving cells; these improved production strains can be subjected again to this process. Strain improvement can likewise frequently be achieved by incorporating techniques of molecular biology. A further important approach is optimizing the production medium, whose components and quantitative composition must be such that a maximum product yield is achieved.
  • the fermentation procedure can also contribute to an increase in yield by exposing the producer organism to the optimum conditions for growth and product formation with respect to oxygen supply, temperature, pH, sheer stress, etc.
  • the present invention relates to the last-mentioned optimization strategy, i.e. to improving the fermentation conditions.
  • the osmolality of the fermentation solution--a parameter which is not usually taken into account in microbial fermentation-- has a very considerable effect on the final yield of the acarbose fermentation.
  • the critical osmolality range is not at all in extreme ranges, but at moderate osmolalities between e.g. 200 mosmol/kg and e.g. 600 mosmol/kg, i.e. at a range which is frequently achieved in nutrient solutions for culturing microorganisms.
  • Osmolalities in this range can usually be termed completely physiological, since human blood, for example, has a value of approximately 400 mosmol/kg. Astonishingly, it has been found that not only low nutrient solution osmolalities, e.g. ⁇ 200 mosmol/kg, but also higher nutrient solution osmolalities, e.g. >600 mosmol/kg, lead to significantly lower productivities, and frequently acarbose cultures under such conditions even exhibit no product formation at all.
  • control strategy On the basis of the pronounced osmolality dependency of the productivity of the acarbose-forming organism, a new control strategy was developed for the fermentation of the secondary metabolite acarbose, which control strategy has not been used to date in comparable microbial fermentations, in particular in the industrial sector.
  • the principle of this control strategy is to keep the osmolality in the desired optimum range by the addition, to be carried out in a suitable manner, of osmotically active substrates.
  • the substrates can be added either portionwise at a time or continuously to a fermentation carried out as fed-batch process.
  • the osmotically active substrates in question are preferably substances which promote the growth of the cultured producer organism. These include especially C sources, N sources and salts. Either individual substrates or mixtures of substrates can be fed to a culture for osmolality stabilization.
  • FIG. 1 depicts the rate of acarbose formation as a function of osmolality.
  • FIG. 2 depicts acarbose content as a function of osmolality after four days of fermentation.
  • FIG. 3 depicts the change in osmolality during the course of various fermentations.
  • FIG. 4 depicts the change in osmolality during the course of various fermentations when a 1.5-fold nutrient solution is added a little at a time.
  • FIG. 5 depicts the change in osmolality during the course of various osmotically controlled fermentations.
  • FIG. 6 depicts the change in osmolality during the course of a fed batch and continuous fermentation.
  • FIG. 7 depicts the rate of acarbose formation during the course of a fed batch and continuous fermentation.
  • the present invention therefore comprises two essential aspects:
  • a control strategy whose aim is the maintenance of a defined range for the osmolality in the culture solution of an acarbose fermentation.
  • a method for maintaining the desired osmolality range characterized in that substrates are added as single portions at a time or continuously in the context of a fed-batch fermentation or a complete nutrient solution is added in the context of a fully continuous fermentation.
  • nutrient solution compositions can successfully be used for the acarbose fermentation (Frommer et al. DE 26 14 393).
  • nutrient solutions containing carbon sources, vitamins and trace elements, salts and buffer substances are expedient to use nutrient solutions containing carbon sources, vitamins and trace elements, salts and buffer substances.
  • a suitable carbon source is maltose, which forms a structural element of the acarbose molecule.
  • Suitable nitrogen sources are individual amino acids, e.g.
  • phosphates and iron salts are supplied to the nutrient solution by the complex nutrient solution substrates and/or by tap water. If demineralized water was used, it was expedient to add a trace element concentrate.
  • the pH in the physiological range, that is between pH 5 and 8, and to supply the culture with sufficient oxygen, so that limitation is avoided.
  • the optimum productivities were attained in the temperature range around 30° C. Since the acarbose producer is a filamentous bacterium, it is further advantageous to avoid extremely high stirrer speeds in stirred-tank fermentations, and thus to avoid sheer forces which are no longer tolerated.
  • the influence of osmolality on the acarbose productivity suggests that a fermentation should be able to be successfully optimized if the osmolality during the fermentation can be kept in a favourable range.
  • the course of the osmolality during the culturing of a microorganism is determined, on the one hand, by the consumption of osmotically active substrates from the nutrient solution and, on the other hand, by the formation of osmotically active products which are released into the nutrient solution during growth.
  • the course shown in FIG. 3 results: the osmolality at the beginning of fermentation is approximately 500 mosmol/kg, i.e. a value which already induces a slight inhibition of productivity.
  • the osmolality decreases, passes through the optimum range and then reaches values which again lead to a fall in productivity.
  • the aim of the addition of nutrient solution substrates to a microorganism culture is to produce a defined metabolic state which is produced by the substrate concentration. Attempts are frequently made in the course of this either to avoid substrate limitation or to produce a defined substrate limitation.
  • the aim of the control is to maintain a defined favourable osmolality range by addition of osmotically active nutrient solution constituents; at the same time, however, it was necessary to take care that no disadvantageous effects due to unintentionally caused excessive or excessively unbalanced substrate concentrations were produced by the addition of substrates.
  • the addition of fresh nutrient solution a little at a time is a process which is technically simple to carry out.
  • the method has the disadvantage that the osmolality is only adapted in stages, and the addition of relatively large amounts of fresh substrates can, in some circumstances, have undesirable effects on the regulation of biosyntheses.
  • the latter aspect is of importance, in particular, in the case of biosynthetic pathways which relate to secondary metabolism.
  • the addition of fresh nutrient solution a little at a time was carried out on a laboratory scale in shaken flasks.
  • the continuous addition of a nutrient solution during the fermentation was carried out and tested on the pilot scale.
  • the process is described in Example 2.
  • the nutrient substrate used was, by way of example, the carbon source used normally in the nutrient solution (starch hydrolysate).
  • Other nutrient solution components (nitrogen sources, salts) or a combination of a plurality of nutrient solution components could also have been used in the same manner.
  • the osmolality of the culture broth could be kept in the favourable range from approximately 350 to approximately 450 mosmol/kg (FIG. 5). It can clearly be seen that it was possible to prevent the decrease in osmolality at the start of the fermentation by beginning the continuous feed approximately 40 hours into the fermentation.
  • Example 3 describes the fully continuous fermentation procedure for osmolality control.
  • the fully continuous fermentation of secondary metabolites is not possible in principle on many occasions since, owing to regulatory phenomena in metabolism, maximum productivity is not achieved until after growth has substantially or completely ceased.
  • parallelism between growth and product formation is an obligatory precondition for a continuous culture to be feasible. Therefore, it must be considered to be absolutely surprising that in the case of acarbose fermentation a fully continuous mode of operation could be carried out successfully.
  • FIG. 6 shows that the osmolality in the culture broth could be kept in the favourable range by the continuous process procedure.
  • the productivity was successfully kept at the maximum value for a batch fermentation over several changes of volume.
  • the osmolality optimum is a strain-specific parameter. Different high-performance strains produced by strain improvement techniques may differ in their osmolality optimum. It may even be the aim of strain improvement to produce high-performance mutants having a changed osmolality optimum.
  • the osmolality values mentioned in the description of the present invention are therefore exemplary and apply to the production strain used.
  • the osmolality optimum must be determined afresh for each newly produced high-performance mutant and the osmotically controlled fermentation must be carried out so as to attempt to maintain the optimum osmolality in the described manner.
  • the acarbose producer strain was cultured in 1 l shaken flasks in 90 ml of the following nutrient solution: starch hydrolysate 100 g/l, yeast extract 7 g/l, casein hydrolysate 3 g/l, CaCO 3 3 g/l, K 2 HPO 4 3 g/l, tap water, pH 6.9.
  • the nutrient solution was sterilized in an autoclave for 10 min at 121° C., then inoculated with a seed culture and incubated at 30° C. and a shaker frequency of 250 rpm. 20 ml each time of a 1.5-fold concentrated nutrient solution of the composition specified above were added after 48 and 72 hours, or after 48 and 96 hours.
  • the feed solution was sterilized in the autoclave for 10 min at 121° C.
  • the osmolality was determined once a day by measuring the freezing point depression; the acarbose content was determined once a day by HPLC.
  • the acarbose producer strain was cultured in the 3000 l fermenter in 1600 l of the following nutrient solution: starch hydrolysate 100 g/l, yeast extract 7 g/l, casein hydrolysate 3 g/l, CaCO 3 3 g/l, K 2 HPO 4 3 g/l, tap water, pH 6.9.
  • the nutrient solution was sterilized (150° C., 52 sec) in a continuous process, filled into the previously sterilized fermenter, inoculated with a seed culture produced in a 300 l fermenter and fermented under the following conditions: temperature: 31° C., head space pressure: 1.0 to 1.8 bar.
  • the acarbose producer strain was cultured in a 3000 l fermenter in 1600 l of the following nutrient solution: starch hydrolysate 100 g/l, L-asparagin.2 H 2 O 20 g/l, K 2 HPO 4 3 g/l, MgSO 4 .7 H 2 O 2 g/l, FeCl 3 .6 H 2 O 1 g/l, Mg 3 (PO 4 ) 2 .8 H 2 O 2 g/l, MnCl 2 .4 H 2 O 0.1 g/l, CoCl 2 .6 H 2 O 0.1 g/l, ZnCl 2 0.1 g/l, tap water, pH 6.8.
  • the nutrient solution was sterilized in a continuous process (150° C., 52 sec), filled into the previously sterilized fermenter, inoculated with a seed culture produced in a 300 l fermenter and fermented under the following conditions: temperature: 31° C., head space pressure: 1.0 to 1.8 bar. Stirring: 150 to 220 rpm, aeration rate: 500 to 1000 l/min. From the 48th hour, a starch hydrolysate solution was continuously fed at a feed rate of approximately 3.2 l/hour; the solution contained 163 kg of starch hydrolysate in tap water (final volume: 233 l) and had been sterilized for 20 min at 121 to 125° C.

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US08/924,157 1996-09-13 1997-09-05 Osmotically controlled fermentation process for the preparation of acarbose Expired - Lifetime US6130072A (en)

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DE19637591 1996-09-13
DE19637591A DE19637591A1 (de) 1996-09-13 1996-09-13 Osmokontrolliertes Fermentationsverfahren zur Herstellung von Acarbose

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JP (2) JP4623766B2 (ja)
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CN (1) CN1113966C (ja)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6849609B2 (en) 2001-04-10 2005-02-01 James U. Morrison Method and composition for controlled release acarbose formulations
CN115161365A (zh) * 2022-09-08 2022-10-11 上海现代制药股份有限公司 一种提高阿卡波糖产量的发酵工艺
WO2023109728A1 (zh) * 2021-12-13 2023-06-22 杭州中美华东制药江东有限公司 一种提高阿卡波糖生物发酵水平的方法

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DE19844924A1 (de) * 1998-09-30 2000-04-06 Bayer Ag Immobilisierte Zellen von Actinoplanes acarbosefaciens SE 50/110, Immobilisierungsverfahren und Verwendung des Immobilisats zur Herstellung von Acarbose
CN101603066B (zh) * 2008-06-13 2013-06-05 上海医药工业研究院 一种阿卡波糖的制备方法
CN102220396B (zh) * 2011-04-27 2013-07-24 江西农业大学 阿卡波糖简易的发酵方法
CN102559814B (zh) * 2012-03-02 2015-11-25 丽珠集团新北江制药股份有限公司 一种制备阿卡波糖的方法
CN112048532B (zh) * 2020-09-18 2022-07-15 山东鲁抗医药股份有限公司 一种发酵生产阿卡波糖的方法
CN112646850A (zh) * 2021-01-26 2021-04-13 石药集团圣雪葡萄糖有限责任公司 一种提高阿卡波糖发酵产量的方法

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US4062950A (en) * 1973-09-22 1977-12-13 Bayer Aktiengesellschaft Amino sugar derivatives
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6849609B2 (en) 2001-04-10 2005-02-01 James U. Morrison Method and composition for controlled release acarbose formulations
WO2023109728A1 (zh) * 2021-12-13 2023-06-22 杭州中美华东制药江东有限公司 一种提高阿卡波糖生物发酵水平的方法
CN115161365A (zh) * 2022-09-08 2022-10-11 上海现代制药股份有限公司 一种提高阿卡波糖产量的发酵工艺
CN115161365B (zh) * 2022-09-08 2023-01-06 上海现代制药股份有限公司 一种提高阿卡波糖产量的发酵工艺

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KR19980024611A (ko) 1998-07-06
CA2215605C (en) 2007-05-08
EP0829541A2 (de) 1998-03-18
HU223576B1 (hu) 2004-09-28
JP4623766B2 (ja) 2011-02-02
ES2217354T3 (es) 2004-11-01
HU9701539D0 (en) 1997-10-28
PT829541E (pt) 2004-09-30
KR100463738B1 (ko) 2005-05-03
HUP9701539A2 (hu) 1998-07-28
IL121733A (en) 2001-05-20
IL121733A0 (en) 1998-02-22
EP0829541B1 (de) 2004-04-21
DE19637591A1 (de) 1998-03-19
EP0829541A3 (de) 1999-12-08
CN1178837A (zh) 1998-04-15
JPH10127298A (ja) 1998-05-19
DE59711536D1 (de) 2004-05-27
DK0829541T3 (da) 2004-07-19
ATE264919T1 (de) 2004-05-15
CA2215605A1 (en) 1998-03-13
JP2008054688A (ja) 2008-03-13
CN1113966C (zh) 2003-07-09
TW349124B (en) 1999-01-01

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